Vitamins and hormones, volume 101

Cover photo credit: Hayashi, Y., Ito, M Klotho-Related Protein KLrP: Structure and Functions Vitamins and Hormones (2016) 101, pp 1–16 © the American Society for Biochemistry and Molecular Biology Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 125 London Wall, London, EC2Y 5AS, UK First edition 2016 Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our 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any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-804819-1 ISSN: 0083-6729 For information on all Academic Press publications visit our website at https://www.elsevier.com Publisher: Zoe Kruze Acquisition Editor: Mary Ann Zimmerman Editorial Project Manager: Helene Kabes Production Project Manager: Vignesh Tamil Designer: Mark Rogers Typeset by SPi Global, India Former Editors ROBERT S HARRIS KENNETH V THIMANN Newton, Massachusetts University of California Santa Cruz, California JOHN A LORRAINE University of Edinburgh Edinburgh, Scotland PAUL L MUNSON University of North Carolina Chapel Hill, North Carolina JOHN GLOVER University of Liverpool Liverpool, England GERALD D AURBACH Metabolic Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland IRA G WOOL University of Chicago Chicago, Illinois EGON DICZFALUSY Karolinska Sjukhuset Stockholm, Sweden ROBERT OLSEN School of Medicine State University of New York at Stony Brook Stony Brook, New York DONALD B MCCORMICK Department of Biochemistry Emory University School of Medicine, Atlanta, Georgia CONTRIBUTORS C.R Abraham Boston University School of Medicine, Boston, MA, United States K Akasaka-Manya Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan P Aljama Instituto Maimo´nides de Investigacio´n Biome´dica de Co´rdoba (IMIBIC), Universidad de Co´rdoba/Hospital Universitario Reina Sofı´a, Co´rdoba, Spain P Buendı´a Instituto Maimo´nides de Investigacio´n Biome´dica de Co´rdoba (IMIBIC), Universidad de Co´rdoba/Hospital Universitario Reina Sofı´a, Co´rdoba, Spain J Carracedo Instituto Maimo´nides de Investigacio´n Biome´dica de Co´rdoba (IMIBIC), Universidad de Co´rdoba/Hospital Universitario Reina Sofı´a, Co´rdoba, Spain C.D Chen Boston University School of Medicine, Boston, MA, United States M Deărmaku-Sopjani University of Prishtina, Prishtineă, Republic of Kosova T Endo Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan T Fu University of Illinois at Urbana-Champaign, Urbana, IL, United States Y Hayashi Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan M.C Hu Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States C.-L Huang University of Texas Southwestern Medical Center, Dallas, TX, United States M Ito Faculty of Agriculture, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan M Kawai Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan xi xii Contributors J.K Kemper University of Illinois at Urbana-Champaign, Urbana, IL, United States D.M Kilkenny Institute of Biomaterials and Biomedical Engineering; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada S Kinoshita Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan H Manya Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan D Modan-Moses The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan; Tel Aviv University, Tel Aviv, Israel P.C Mullen Boston University School of Medicine, Boston, MA, United States J.A Neyra Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States R Ramı´rez Alcala´ de Henares University, Madrid, Spain J.V Rocheleau Institute of Biomaterials and Biomedical Engineering; Banting and Best Diabetes Centre, University of Toronto; Toronto General Research Institute, University Health Network, Toronto, ON, Canada T Rubinek Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel M Sopjani University of Prishtina, Prishtineă, Republic of Kosova T Tucker-Zhou Boston University School of Medicine, Boston, MA, United States I Wolf Institute of Oncology, Tel Aviv Sourasky Medical Center; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Y.-L Wu University of Texas Southwestern Medical Center, Dallas, TX, United States J Xie University of Texas Southwestern Medical Center, Dallas, TX, United States E Zeldich Boston University School of Medicine, Boston, MA, United States PREFACE Klotho (feminine) means “spinner” in Greek and refers to one of the three fates (Moirai) that spin the thread of life Klotho exists as an insoluble, membrane form or as soluble forms generated by enzymatic cleavage of the membrane form The membrane full-length form (mass of 130 kDa) has two extracellular glycosyl hydrolase domains (KL1 and KL2) plus a 20-amino acid transmembrane domain and a 9-amino acid intracellular domain The soluble forms that can circulate in the bloodstream have either KL1 or Kl1 plus KL2 domains and, once in the circulation, they function as hormones There is also a secreted Klotho that is generated by alternative splicing of mRNA; it contains 549 amino acids and has a mass of 65 kDa Both the soluble and the secreted forms of Klotho regulate the TRPV5 channel and the kidney medullary potassium channel (ROMK1) Likely, there exist still other forms of Klotho In the mouse, Klotho gene mutation is the single gene mutation known to generate premature aging Klotho is synthesized in several tissues, primarily in the kidney and brain choroid plexus The actions of Klotho are related to other factors: vitamin D induces kidney Klotho and with the activity of vitamin D, the systems of growth, development, antioxidation, and homeostasis are maintained and promoted Klotho interacts with other important hormones and growth factors Presumably, Klotho lengthens the life span by delaying the chronic diseases of aging The prospect of the use of Klotho in the treatment of human diseases, especially kidney disease and others, is enthralling In this volume, the X-ray structures of Klotho are reported as well as the topics described above together with its many roles in rescuing the disease processes In the first chapter, Hayashi and Ito report on “Klotho-related protein KLrP: structure and functions.” This is followed by the work of Kilkenny and Rocheleau: “The FGF21 receptor signaling complex: Klothoβ, FGFR1c, and other regulatory interactions.” Furthering the basic aspects of Klotho actions, Sopjani and Deărmaku-Sopjani describe Klothodependent cellular transport regulation. On the interactions of Klotho and other factors, Rubinek and Modan-Moses introduce “Klotho and the growth hormone/insulin-like growth factor axis: novel insights into complex interactions.” Then follows a report on “Klotho prevents translocation of NFκB” by Buendı´a, Ramı´rez, Aljama, and Carracedo Kinoshita and xiii xiv Preface Kawai describe “The FGF23/Klotho regulatory network and its roles in human disorders.” “MicroRNA-34a and impaired FGF19/21 signaling in obesity” by Fu and Kemper increases the span of Klotho involvement In Chapter 8, Rubinek and Wolf introduce “The role of alpha-Klotho as a universal tumor suppressor.” Positive actions of Klotho are emphasized in “Klotho is a neuroprotective and cognition-enhancing protein” by Abraham, Mullen, Zhou, Chen, and Zeldich The last three chapters involve kidney disease and fallout to the heart In the first of these, Akasaka-Manya, Manya, and Endo write on “Function and change with aging of α-Klotho in the kidney.” “αKlotho and chronic kidney disease” is described by Neyra and Hu Finally, Xie, Wu, and Huang report on “Deficiency of soluble αKlotho as an independent cause of uremic cardiomyopathy.” The illustration on the cover is the previously published version (Journal of Biological Chemistry) of the X-ray structure of Klotho-related protein, an alternative to Fig 3A reported in Chapter by Hayashi and Ito: “Klothorelated protein KLrP: structure and functions.” Helene Kabes of Elsevier (Oxford, UK) was, as usual, a central person in the development of the publication process The collaboration of Reed-Elsevier, Chennai, India, in the development of galley proofs and final corrections of these proofs leading directly to publication, was invaluable GERALD LITWACK Toluca Lake, North Hollywood, CA March 9, 2016 CHAPTER ONE Klotho-Related Protein KLrP: Structure and Functions Y Hayashi*, M Ito†,1 *Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan † Faculty of Agriculture, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan Corresponding author: e-mail address: makotoi@agr.kyushu-u.ac.jp Contents Introduction The Functions and Crystal Structure of KLrP 2.1 Metabolic Pathway for GSLs Involving acid GCase GBA1 2.2 Identification of KLrP as a Novel Cytosolic Neutral GCase 2.3 KLrP Crystal Structure 2.4 Mammalian GCases Other than GBA1 and KLrP (GBA3) KLrP and GD Conclusions and Perspectives Acknowledgments References 3 10 11 14 14 15 Abstract Klotho (KL) family proteins share one or two glycoside hydrolase (GH) motifs homologous to GH family However, the biological significance of GH motifs in KL family proteins remains elusive We describe here that KL-related protein (KLrP), which is composed of a single GH motif, is a cytosolic β-glucocerebrosidase (GCase, EC 3.2.1.145) We detected a neutral conduritol B epoxide (CBE)-insensitive glucosylceramide (GlcCer)-degrading activity in the cytosol fractions of human fibroblasts, rat brains, and zebrafish embryos KL family proteins emerged as a potent candidate for the neutral GCase using a bioinformatics approach Recombinant human KLrP, but not α-KL, β-KL, or KLPH, exhibited GCase activity with a neutral pH optimum in the presence of CBE We solved the crystal structures of KLrP and a KLrP mutant (E165Q) in complex with glucose, which indicate that KLrP forms a (β/α)8TIM barrel structure with the double-displacement mechanism of the retaining β-glycosidase Furthermore, knockdown of endogenous KLrP in CHOP cells using small interfering RNA (siRNA) decreased the CBE-insensitive neutral GCase activity and increased the cellular levels of GlcCer, which suggests that KLrP is involved in a novel GlcCer catabolism pathway A KLrP D106N mutant was discovered in patients with severe Gaucher disease; however, this mutation did not affect the GCase activity of KLrP Vitamins and Hormones, Volume 101 ISSN 0083-6729 http://dx.doi.org/10.1016/bs.vh.2016.02.011 # 2016 Elsevier Inc All rights reserved Y Hayashi and M Ito ABBREVIATIONS CBE conduritol B epoxide GalCer galactosylceramide GBA glucosidase, beta, acid GCase β-glucocerebrosidase (β-glucosylceramidase) GD Gaucher disease GH glycoside hydrolase GlcCer glucosylceramide GlcT-1 UDP-glucose: ceramide glucosyltransferase-1 GSL glycosphingolipid KL klotho KLrP Klotho-related protein LacCer lactosylceramide LPH lactase-phlorizin hydrolase 4MU 4-methylumbelliferyl NBD 4-nitrobenzo-2-oxa-1,3-diazole WT wild type INTRODUCTION Phenotypes resembling human aging were observed in transgenic mice that overexpressed the type I sodium–proton exchanger (Kuro-o et al., 1997) Kurosu et al (2005) refer to this mutant as klotho (α-KL), who is the Greek goddess that spins the thread of life Disrupting α-KL resulted in a shorter life span for the mice; conversely, overexpression of α-KL produces an extended life span Therefore, α-KL is likely involved in controlling aging The α-KL protein is composed of two glycoside hydrolase (GH) motifs that are similar to enzymes in GH family Recombinant human α-KL protein (human IgG1 Fc chimera protein) exhibits β-glucuronidase activity; however, two potentially catalytic glutamic acids in the GH motifs were mutated to asparagine and serine, respectively (Tohyama et al., 2004) Natural steroid β-glucuronides, such as β-estradiol 3-β-D-glucuronide, estrone 3-β-D-glucuronide, and estriol 3-β-D-glucuronide, competitively inhibit the glucuronidase activity of the α-KL protein The α-KL protein might convert inactive glucuronylated steroids into their active forms after removing the terminal β-glucuronic acid This process may be involved in maintaining calcium homeostasis In addition, the α-KL protein seems to feature sialidase, which catalyzes the removal of terminal sialic acids from N-linked glycans on the TRPV5 calcium channel (Cha et al., 2008) Removing the terminal sialic acids Klotho-Related Protein KLrP exposed the disaccharide galactose-N-acetyl-glucosamine, which is a galectin-1 ligand Binding between galectin-1 and the N-glycans inhibits endocytosis of the TRPV calcium channel, which is retained at the plasma membrane surface These results suggest that the α-KL protein regulates the turnover of TRPV at the plasma membrane; however, the biochemical evidence supporting the notion that the α-KL protein is a sialidase remains elusive Leunissen et al (2013) reported that α-KL and sialidase regulated TRPV5 membrane stabilization in a different manner, suggesting that α-KL does not possess sialidase activity Proteins that are structurally related to the α-KL protein have been discovered and designated the β-KL protein (Ito et al., 2000), KLPH (Ito, Fujimori, Hayashizaki, & Nabeshima, 2002), and Klotho-related protein (KLrP) (Yahata et al., 2000) The β-KL protein features two GH domains, similar to the α-KL protein, whereas KLPH and KLrP only feature one GH domain The β-KL protein, KLPH, and KLrP show 41%, 36%, and 41% identity with α-KL at the amino acid level, respectively KLrP (formerly referred to as GBA3) was previously identified as a human cytosolic β-glucosidase that can hydrolyze nonphysiological glycosides, such as 4-methylumbelliferyl (4MU)-glycosides, pNP-glycosides, and flavonoid glycosides (de Graaf et al., 2001) However, endogenous substrates for KLrP had not been identified until we reidentified KLrP as a neutral β-glucocerebrosidase (GCase) that can hydrolyze glucosylceramide (GlcCer) (Hayashi et al., 2007) GlcCer is a precursor for various glycosphingolipids (GSLs) and is synthesized on the cytosolic face of the Golgi apparatus with UDP-glucose: ceramide glucosyltransferase-1 (GlcT-1) (Ichikawa & Hirabayashi, 1998) In this review article, we describe the structure and functions of KLrP as well as discuss the relationship between KLrP and Gaucher disease (GD) THE FUNCTIONS AND CRYSTAL STRUCTURE OF KLrP 2.1 Metabolic Pathway for GSLs Involving acid GCase GBA1 GSLs with different glycan structures are present in vertebrate plasma membranes and are synthesized from the precursors GlcCer and galactosylceramide (GalCer) by GlcT-1 and GalCer synthase, respectively GlcCer is ubiquitously distributed in mammalian tissues, while the GalCer distribution is restricted, eg, in the myelin oligodendrocytes of the brain GlcT-1 is mainly located on the Golgi apparatus where the active site faces the cytoplasmic side (Ichikawa & Hirabayashi, 1998) On the other hand, Y Hayashi and M Ito GalT-1 is mainly located on the ER where the active site faces the luminal side (Sprong et al., 1998) Thus, GlcCer is synthesized on the cytosolic face, whereas GalCer is on the luminal face The GlcCer generated is then translocated to the luminal side of the Golgi membrane, where it is converted into lactosylceramide (LacCer) by LacCer synthase LacCer synthesis is followed by the generation of complex GSLs through a step-by-step extension of sugar chains by corresponding glycosyltransferases In contrast, GalCer is converted into GM4 and sulfatide by sialylation and sulfation, respectively; further sugar chain extension does not occur in mammals Finally, GSLs are transported through the trans-Golgi network to the plasma membrane where the sugar moiety faces extracellular space, and the ceramide moiety is embedded in the upper layer of the membrane GSLs at the plasma membrane are then internalized in endocytic vesicles and transported to the lysosome, where the corresponding acid GHs hydrolyze GSLs through a step-by-step removal of sugar chains facilitated by specific activator proteins, so-called saposins GBA1, which is also known as acid GCase, hydrolyzes GlcCer to the ceramide and glucose facilitated by saposin C in the lysosomes Conduritol B epoxide (CBE) specifically and irreversibly inhibits GBA1 activity An inherited GBA1 deficiency causes GD, which is the most common lysosomal storage disease and is characterized by GlcCer accumulation in the lysosomes of laden tissue macrophages However, GlcCer accumulation in other cell types is not clear in patients with GD despite a significant decrease in GBA1 activity, which suggests an alternative catabolic pathway for GlcCer (Barranger & Ginns, 1989; Beutler & Grabowski, 2001) 2.2 Identification of KLrP as a Novel Cytosolic Neutral GCase During the LacCer synthase activity assay in human fibroblasts using C6-4nitrobenzo-2-oxa-1,3-diazole (NBD)-GlcCer as an acceptor substrate and UDP-Gal as a donor substrate at pH 6.0, C6-NBD-Cer was detected through HPLC in addition to the expected product C6-NBD-LacCer The generation of C6-NBD-Cer was significantly lower but was not completely eliminated by adding CBE, which is a potent GBA1 inhibitor The activity of the GlcCer-hydrolyzing enzyme reached a maximum at pH 6–7 in the presence of CBE and was mainly recovered in the cytosolic fraction of the fibroblasts Cytosolic proteins that can hydrolyze GlcCer have not been reported Interestingly, C6-NBD-GlcCer hydrolysis to C6-NBD-Cer in the presence of CBE was observed in lysates not only from 324 J Xie et al 4.3.2 Klotho Downregulates TRPC6 in Heart: Genetics Evidence A possible regulatory relation between Klotho and TRPC6 was investigated by Xie et al (Xie et al., 2012, 2015) Klotho-deficiency in mice aggravated ISO-induced cardiac hypertrophy, and also the increases of TRPC6 expression in heart Conversely, Klotho overexpression in mice attenuated the ISO-induced increases in cardiac Trpc6 mRNA expression Deletion of Trpc6 in mice partially protected against ISO-induced cardiac remodeling In a Klotho/Trpc6 double-knockout mouse model, absence of TRPC6 completely prevented the exaggerated ISO-induced cardiac hypertrophy caused by Klotho deficiency Mice with cardiac-specific overexpression of TRPC6 (C6-Tg) develop spontaneous cardiac hypertrophy and have shortened life span (Kuwahara et al., 2006) When they were crossed with transgenic mice-overexpressing klotho (Kl-Tg), the resulting double transgenic mice (C6-Tg, Kl-Tg) had ameliorated cardiac hypertrophy and improved survival curve, compared to C6-Tg mice Also, in uremic cardiomyopathy induced by CKD, Trpc6 gene expression and channel activity were upregulated This Trpc6 upregulation was further aggravated in klotho-deficient CKD heart, compared with WT CKD heart These genetic studies suggested that Klotho protects the heart by inhibiting cardiac TRPC6 4.3.3 Soluble Klotho Inhibits TRPC6 Activity by Downregulating Its Exocytosis In vitro assays have also been performed to verify that Klotho inhibits TRPC6 activity in cardiomyocytes and to investigate the underlying mechanism TRPC6 channel activity was measured in freshly isolated ventricular myocytes by whole-cell patch-clamp recording It was identified as current increase above baseline in WT cardiomyocytes after ISO treatment, and in Trpc6-overexpressing cardiomyocytes The current increase by ISO treatment was eliminated in Trpc6-knockout hearts The ISO-induced increase in currents was prevented in cardiomyocytes of klothooverexpressing transgenic mice, similar to the pattern observed in Trpc6knockout cardiomyocytes Acute addition of soluble Klotho to culture media decreased TRPC6-mediated currents in WT cardiomyocytes after ISO treatment and that in Trpc6-overexpressing cardiomyocytes These results confirmed that soluble Klotho directly inhibits TRPC6 activity in cardiac myocytes Soluble Klotho also inhibits TRPC6 currents in HEK Deficiency of Soluble α-Klotho 325 cells expressing recombinant TRPC6 Biotinylation assays of the TRPC6expressing HEK cells revealed that the Klotho treatment decreased cell surface abundance of TRPC6 Blocking exocytosis by v-SNARE inhibitor tetanus toxin decreased TRPC6 currents in these cells, and prevented further inhibition by soluble Klotho, suggesting that the major action of Klotho on TRPC6 is by blocking exocytosis On the other hand, blocking endocytosis using a dominant-negative dynamin did not affect the ability of Klotho to inhibit TRPC6 (Xie et al., 2012) It has been reported that cell surface abundance of TRPC channels is regulated by exocytosis, which is under the control of phosphoinositide3-kinase (PI3K) signaling pathways (Bezzerides, Ramsey, Kotecha, Greka, & Clapham, 2004) Soluble Klotho is known to inhibit PI3K signaling by insulin and insulin-like growth factors (IGF), which contributes to the antiaging and tumor suppression effects of Klotho (Ch^ateau, Araiz, Descamps, & Galas, 2010; Kurosu et al., 2005; Wolf et al., 2008) When analyzed in TRPC6-expressing HEK cells, IGF1 promoted TRPC6 currents, while addition of soluble Klotho inhibited this IGF1-stimulated TRPC6 current Moreover, PI3K inhibitor wortmannin decreased TRPC6 currents stimulated by IGF1, and abrogated the TRPC6-inhibiting effect of Klotho In ISO-treated cardiac myocytes, the TRPC6 current was decreased by treatment of wortmannin to the similar levels of that was treated by soluble Klotho and exocytosis blocker tetanus toxin Any combination of the three did not further decrease TRPC6 current These results indicate that soluble Klotho inhibits IGF1- and PI3K-dependent exocytosis of TRPC6 (Xie et al., 2012) CONCLUSION Recent new evidences have shown that soluble Klotho inhibits a cardiac Ca2+ channel TRPC6 by downregulating IGF1- and PI3K-dependent TRPC6 exocytosis, and protects the heart against stress-induced pathological hypertrophy and remodeling (Fig 4) Decreased level of circulating soluble Klotho in CKD is an important cause of uremic cardiomyopathy independent of FGF23 and phosphate, opening new avenues for treatment of this disease 326 J Xie et al Fig Soluble Klotho protects the heart by inhibiting IGF/PI3K-dependent TRPC6 exocytosis Stresses (ISO overstimulation, uremia, etc.) cause an abnormal intracellular Ca2+ signaling, which activates calcineurin and NFAT, thereby inducing cardiac hypertrophy and remodeling, as well as Trpc6 gene expression Upregulation of TRPC6 provides a feed-forward loop that amplifies and sustains the 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sulphate-induced myocardial hypertrophy Journal of the American Society of Nephrology, 26(10), 2434–2446 http://dx.doi.org/10.1681/ASN.2014060543 INDEX Note: Page numbers followed by “f ” indicate figures, and “t” indicate tables A Action potential (AP), 70, 225–226 Age-related cognitive decline (ARCD), 225, 227, 230–231 α-Klotho, 152 calpain aberrant calcium transport, 248–249 for aging-related disorders, 248 kidney, overactivation in, 246–248, 247f deficiency (see Chronic kidney disease (CKD)) internal repeats, 240 in kidney, 240–241 mouse model, 240 nonsulfated HNK-1 glycan, 249–250, 251f phosphate and vitamin D FGF23, 241–245, 243f Na+,K+-ATPase, 243f, 245–246 Alzheimer’s disease (AD), 217, 225–226, 230–231 Anorexia nervosa (AN), 101–102, 102t Antioxidant, 220–221 ARCD See Age-related cognitive decline (ARCD) Autosomal dominant hypophosphatemic rickets (ADHR), 163, 241–242 B Biotinylation assays, 324–325 βKL See β-Klotho (βKL) β-Klotho (βKL), 152 domains, 37 FGF19, 179–182 FGF21 in adipose tissue, 184–186, 185f in liver, 183–184 orchestrates metabolism, 187 pancreatic β-cell function, 186–187 prolonged starvation, 187 synthesis of, 182 and FGFR1 interaction, 36–37 heterodimers, with FGFR1c/4 aggregation process, 41–42 allosteric/rotational model, 38–40 competitive model, 40–41 energetically favorable 2:2:2 model, 37–38 FGF21:FGFR1:KLB, 39f, 41 FGFR1c, co-expression of, 39f, 40–41 1:1 FGFR1:KLB heterocomplex, 39f, 40–41 HSPGs function, 37–38 ligand stimulation, 38–40 putative receptor stoichiometry, 38–40, 39f in liver, 180–181 of receptors, 19–21, 20t structure, 21–22, 22f tissue expression, 22–23 Bone marrow mesenchymal stem cells (BMMSCs), 71–74 C Calpain aberrant calcium transport, 248–249 for aging-related disorders, 248 kidney, overactivation in, 246–248, 247f Calpastatin, 246–247 Cancer-specific survival (CSS), 201–202 Cardiac hypertrophy calcium channels, 70 characterization, 272 CKD models, 274 hERG channels, 70 mechanism, in CKD patients CKD-specific risk factors, 314, 315f conventional risk factors, 314, 315f IS and p-CS, 317 LV pressure overload, 314 LV volume overload, 314 phosphate retention, 318–319 331 332 Cardiac hypertrophy (Continued ) secondary hyperparathyroidism, 314–316 vitamin D deficiency, 316 prevalence of, 313 stress-induced, 274–275 TRPC6, 69–70 vascular calcification and prevention, 135 Cardiovascular disease (CVD), 134–135, 137–139 Cholesterol And Recurrent Events (CARE) study, 318 Chronic kidney disease (CKD) biomarker clinical studies, 284, 285t CV disease, 285t, 290 FGF23, 283 functional, 282 injury, 282–283 progressive CKD, 290 cardiac hypertrophy, mechanism of CKD-specific risk factors, 314, 315f conventional risk factors, 314, 315f IS and p-CS, 317 LV pressure overload, 314 LV volume overload, 314 phosphate retention, 318–319 secondary hyperparathyroidism, 314–316 vitamin D deficiency, 316 circulationg, 263 CVD, 137–139 development and progression cell senescence, 264 endothelial dysfunction, 265–266 impaired vasculogenesis, 265–266 reduced ability, 264 renal fibrosis, 266–267 Wnt signaling activity, 264–265 etiology, 261–262 FGF23, 156–157, 165–166 Klotho, low level of, 133 local renal factors, 262–263, 262f mineral metabolism FGF23, 320–321, 321f hyperphosphatemia, 262f, 267–269 hypovitaminosis D, 268f, 270 increased FGF23 levels, 268f, 269–270 Index Klotho protein and shedding model, 319, 319f physiological role, 267, 268f regulate ion transport and growth factor, 319–320 secondary hyperparathyroidism, 268f, 271–272 pathological uremic cardiomyopathy cardiac remodeling, 273–274 CV disease, cause of, 272 indoxyl sulfate-induced myocardial hypertrophy, 275–276 intermediate mediator, 272 risk factors, 272, 273f stress-induced cardiac hypertrophy, 274–275 sources, 260–261, 261f treatment strategy clinical application, 292, 293t epigenetic regulation, 291 upregulation, 293–294 uremic toxins, 135–141 vascular calcification, 139–141 vascular medial calcification calcium and phosphate, 276–277 endothelium cells, 277–279, 278f vascular smooth muscle, 278f, 279–281 Chronic obstructive pulmonary disease (COPD), 141 Chronic Renal Insufficiency Cohort (CRIC), 313 CKD See Chronic kidney disease (CKD) Conduritol B epoxide (CBE), Cox proportional-hazards models, 318 CVD See Cardiovascular disease (CVD) D Dentin matrix protein (DMP-1), 163–164 Diabetes, 141–142 Dietary Pi, 157 E Endocrine FGF21 FGF family, 28–29, 30t FGF structure, 29–31, 31f vs paracrine FGFs, 31–32, 32t structure, 31–32, 31f tissue expression, 31f, 32–34 Index Endothelium cells (ECs) autocrine/paracrine mode, 278f, 279 FMD, 277 functional vascular tone and oxidative stress, 277 high phosphate/uremic solutes, 277 regulation, 277 treatment, 277–279 Epigenetic mechanisms, 93–94 Estradiol (E2), 223 F FGF19 See Fibroblast growth factor 19 (FGF19) FGF21 See Fibroblast growth factor 21 (FGF21) FGF23 See Fibroblast growth factor 23 (FGF23) FGFR See Fibroblast growth factor receptor (FGFR) FGF21 receptor signaling complex cell membrane, FGF21 stimulation, 19 description, 18 ECM regulation, 43f, 44–45 endocrine FGF family, 28–29, 30t FGF structure, 29–31, 31f vs paracrine FGFs, 31–32, 32t structure, 31–32, 31f tissue expression, 31f, 32–34 FGFR5, 43f, 45–47 galectin lattice, inactivation of KLB, 42–44, 43f HSPGs, 18–19 KLB domains, 37 and FGFR1 interaction, 34–37 interaction, 34 of receptors, 19–21, 20t stoichiometry (see Heterodimers, with FGFR1c/4) structure, 21–22, 22f tissue expression, 22–23 Fibroblast growth factor 19 (FGF19) miR-34a in liver, 180–181 regulation of, 181–182 333 obesity βKL, 179–180 endocrine hormones, 176, 178–179 FGFR, 178–179 lipid and carbohydrate metabolism, 176 synthesis, 179 Fibroblast growth factor 21 (FGF21) βKL, 179–180 lipid and carbohydrate metabolism, 176 miR-34a in adipose tissue, 184–186, 185f in liver, 183–184 orchestrates metabolism, 187 pancreatic β-cell function, 186–187 prolonged starvation, 187 synthesis of, 182 PPARα, 179 Fibroblast growth factor 23 (FGF23) 1,25(OH)2D3, 64–65 defective phosphate excretion, 268f, 270 FGFR1–Klotho complex, 123, 124f, 125–126 high serum FGF23 levels, 270 hypophosphatemic rickets and osteomalacia, 152–153 KL-dependent pathway, 159–160, 160f, 166–167 KL-independent pathway, 160–161, 166–167 α-Klotho 1,25(OH)2D3, 242–245 FGFR, 241–242, 243f NaPi-IIa and NaPi-IIc, 244–245 serum concentration, 242–244 mutations ADHR, 163 and CKD, 165–166 DMP1 and ENPP1 gene, 163–164 elevations, 164–165 FAM20C gene, 163–164 GALNT3 gene, 165 KLOTHO gene, 165 PHEX, 163–164 NaPi-IIa, 74–76 parathyroid glands, 123, 126 phosphate and calcium regulating hormone, 61–62 334 Fibroblast growth factor 23 (FGF23) (Continued ) phosphaturic factor and calcitrotropic hormone, 271 Pi metabolism, regulation of, 161–162 PTH synthesis and secretion, regulation of, 162 regulation, 156–158, 159f structure, 155, 156f vitamin D metabolism, regulation of, 162 Fibroblast growth factor receptor (FGFR), 61–62, 123, 158, 241–242 FGFR1c tissue expression, 27–28 fibroblast growth factor receptor family, 23–24, 176 structure autoinhibition, 24–26 ligand-binding specificity, FGFR1–3, 26–27 ligand-bound receptor, 24–26 phosphorylation targets, 24–26 signaling cascades, 24–26, 25f Fibroblast growth factors (FGFs), 122–123 Flow-mediated dilatation (FMD), 277 5-fluorouracil (5FU), 206 FoxO (forkhead box), 126–127 G Galactosylceramide (GalCer), 3–4 Gaucher disease (GD) acute neuropathic, 11 definition, 11 D106N mutation, GCase activity, 12, 13f GBA2 activity, 13–14 individual identification, 11–12 KLrP D106N mutant, 12 nonneuropathic, 11 subacute neuropathic, 11 working hypothesis, 11, 12f GD See Gaucher disease (GD) Gemcitabine, 206 GH/IGF-1 axis See Growth hormone/ insulin-like growth factor (GH/IGF-1) axis γ-Klotho, 152 Glucose transporter-1 (GLUT-1), 186 Glycoside hydrolase (GH) motifs, Index Growth hormone/insulin-like growth factor (GH/IGF-1) axis Klotho available tests, 93 diverse mechanisms, 91–92 factor affecting circulating Klotho levels, 93–94 history, 90–91 in humans (see Health and disease states) mice and humans, 94–95 shedding, 94 structure, 90–91 pituitary gland activity, 87–89 autocrine and paracrine regulation, 87, 89 hypothalamic regulation, 87–88 location, 86 mice and humans, 94–95 negative regulator somatostatin, 87, 107f peripheral regulation, 87–89 positive regulator GH-releasing hormone, 87, 107f secretion bFGF activity, 96–97 cultured pituitary adenomas, 95, 96f IGF-1, 95–97, 97f H Health and disease states acromegaly, 104, 105t aging, 103–104 AN, 101–102, 102t females vs males, 97–98 GH deficiency biomarkers, 98 clinical and anthropometric characteristics, 98–99, 99t diagnosis, 98 serum klotho levels and IGF-1, 98–99, 100f stimulation tests, 98–99 sufficient vs deficient children, 100 in obesity, 103 pubertal vs prepubertal children, 97–98 Heterodimers, with FGFR1c/4 aggregation process, 41–42 allosteric/rotational model, 38–40 Index competitive model, 40–41 energetically favorable 2:2:2 model, 37–38 FGF21:FGFR1:KLB, 39f, 41 FGFR1c, co-expression of, 39f, 40–41 1:1 FGFR1:KLB heterocomplex, 39f, 40–41 HSPGs function, 37–38 ligand stimulation, 38–40 putative receptor stoichiometry, 38–40, 39f Human ether-a-go-go (hERG), 70 Human natural killer-1 (HNK-1), 250, 251f Hypermethylation, 93–94 Hyperphosphatemia, 139, 241–242, 244–245, 262f, 267–269, 318–319 Hypothalamic regulation negative regulator, 88 positive regulator, 87 Hypovitaminosis D, 268f, 270 I Indoxyl sulfate (IS) and p-cresyl sulfate (p-CS), 317 Insulin-like growth factor (IGF-1) signaling pathway, 124–125, 154, 207, 208f K KL-dependent pathway, 159–160, 160f Klotho (KL) activities, 198–199, 208f, 209–210 aging, regulation of, 152 β-Klotho, 152 in brain, expression and localization of, 217–219 cancer anticancer activity in vivo, 205 β-catenin, 207–208 circulation, 206–207 IGF-1/PI3K/AKT, 207, 208f malignant tissue vs normal tissue, 200–201, 200f silencing, 202–203 SNP, 203 TGF-β1, 209 tumor aggressiveness and Klotho expression, 201–202 tumor cells in vitro, 204–205 Wnt pathway, 207–208 335 carriers, regulation of aging-induced processes, 74–77 BMMSC, 71–74 EAAT3 and EAAT4, 74 NaPi-IIa, 74–76, 76f NaPi-IIb, 74–76 chemotherapies cisplatin, 205–206 5FU, 206 gemcitabine, 206 CKD (see Chronic kidney disease (CKD)) and cognition aging, 224–226 in hippocampus, 220–221 human cognition, 223–224 Klotho-VS polymorphism, 219, 223–224 LTP, 221–222 neuroendocrine system, 223 neuroinflammation, 226 white matter, 224–226 COPD, 141 CVD, 134–135 diabetes, 141–142 ectodomain shedding, 61–62 expression profile, 153–154 FGF23 (see Fibroblast growth factor 23 (FGF23)) FGFR, 178–179 FoxO activation, 126–127 functions of, 122f aging, regulation of, 198–199 FGF-23, 122–123, 124f, 125–126 insulin/IGF-1 signaling pathway, 154 insulin regulation, 124–125 intracellular signaling regulation, 125 ion exchange processes, 124 gene structure and protein types, 60–61, 61f GH/IGF-1 axis available tests, 93 diverse mechanisms, 91–92 factor affecting circulating Klotho levels, 93–94 history, 90–91 in humans (see Health and disease states) mice and humans, 94–95 336 Klotho (KL) (Continued ) shedding, 94 structure, 90–91 γ-Klotho, 152 in humans, 216–217 ion channels, regulation of CreaT, 76–77 1,25(OH)2D3, 64–65 EAAT3 and EAAT4, 74 galectin-3-binding mechanisms, 68 hERG, 70 KCNQ1/KCNE1, 70–71 platelets activation, 65 ROMK1, 66–68, 67f TRPC-1, 68–69 TRPV2, 69 TRPV5, 64–68 TRPV6, 64–66, 69–70 in kidney, 217 α-Klotho, 152 Klotho-deficient mice, 216 myelination, 227–228 Na+,K+-ATPase, 77–78 neurodegeneration, 228–232 NFκB activation, 131 cellular senescence, 132–134 definition, 128–129 IκBs, 130 inflammation, 128, 129f, 131–132 regulation, 130 Rel homology domain, 129–130 NO production, 127 oligodendrocyte biology, 227–228 oxidative stress, 228–231 structure, 120–122, 121f, 153, 154f, 198–199 transport proteins, 62–63, 71, 72t, 78 TWEAK, 128 Wnt signaling, 127 Klotho-related protein (KLrP) crystal structure catalytic mechanism, 7–9, 8f GBA1, 8f, 9–10 KLrP/Glc substrate-binding cleft, 8f, point mutations, 7–9, 8f GD acute neuropathic, 11 Index definition, 11 D106N mutation, GCase activity, 12, 13f GBA2 activity, 13–14 individual identification, 11–12 KLrP D106N mutant, 12 nonneuropathic, 11 subacute neuropathic, 11 working hypothesis, 11, 12f GH motifs, GSLs, metabolic pathway, 3–4 history, identification CAZy database, 5–7 CBE-insensitive neutral GCase activity, 5–7, 6f C6-NBD-Cer, 4–5 CRISPR-Cas9 system, cytosolic protein, 5–7, 5f GCase activity, 5–7 Hanes–Woolf plots, 5–7 KLrP-deficient cells, LacCer synthase activity assay, 4–5 siRNA, mammalian GCases, 10–11, 10f, 14 natural steroid ß-glucuronides, KLrP See Klotho-related protein (KLrP) L Long-term memory (LTM), 221 Long-term potentiation (LTP), 221–222, 230–231 LVH, 313–314 M μ-Calpain, 248–249 MicroRNAs (miRs) diagnostic potential, 190 therapeutic potential, 187–190, 189t Mineral metabolism, CKD hyperphosphatemia, 262f, 267–269 hypovitaminosis D, 268f, 270 increased FGF23 levels, 268f, 269–270 physiological role, 267, 268f secondary hyperparathyroidism, 268f, 271–272 MiR-34a βKL/FGF19 axis 337 Index in liver, 180–181 regulation of, 181–182 βKL/FGF21 axis in adipose tissue, 184–186, 185f in liver, 183–184 orchestrates metabolism, 187 pancreatic β-cell function, 186–187 prolonged starvation, 187 synthesis of, 182 lipid and glucose metabolism, 177–178 Multiple sclerosis (MS), 217, 225–228, 231 Myelin, 225–226 N Neurodegeneration, 228–232 N-methyl-D-aspartate receptor (NMDAR), 221–222 Nuclear factor κB (NFκB) activation, 131 cellular senescence, 132–134 definition, 128–129 IκBs, 130 inflammation, 128, 129f, 131–132 regulation, 130 Rel homology domain, 129–130 O Obesity FGF19 βKL, 179–180 endocrine hormones, 176, 178–179 FGFR, 178–179 lipid and carbohydrate metabolism, 176 synthesis, 179 FGF21 βKL, 179–180 lipid and carbohydrate metabolism, 176 PPARα, 179 FGF23, 178–179 miRs diagnostic potential, 190 lipid and glucose metabolism, 177–178 therapeutic potential, 187–190, 189t Oligodendrocyte biology, 227–228 Oligodendrocyte progenitor cell (OPC), 227 Osteomalacia, 164–165 Oxidative stress, 127–128, 133–134, 136, 228–231 P Parathyroid hormone (PTH), 126, 156–157, 245–246 Parkinson’s disease (PD), 225–226 Pathological uremic cardiomyopathy cardiac remodeling, 273–274 CV disease, cause of, 272 indoxyl sulfate-induced myocardial hypertrophy, 275–276 intermediate mediator, 272 risk factors, 272, 273f stress-induced cardiac hypertrophy, 274–275 Phosphoinositide-3-kinase (PI3K) signaling pathways, 325 Progression-free survival (PFS), 201–202 R Raine syndrome, 164–165 Reactive nitrogen species (RNS), 228 Reactive oxygen species (ROS), 127, 136–137, 228–229 Rel homology domain, 129–130 Renal cell carcinoma (RCC), 201–202 Renal outer medullary potassium channel (ROMK1), 66–68, 67f ROMK1 See Renal outer medullary potassium channel (ROMK1) ROS See Reactive oxygen species (ROS) S Secondary hyperparathyroidism, 268f, 271–272 Shed ectodomain of Klotho (sKlotho), 216–217 Short-term memory (STM), 221 Single-nucleotide polymorphism (SNP), 203, 223–224 SNP See Single-nucleotide polymorphism (SNP) Stress-induced premature senescence (SIPS), 132 T Transient receptor potential vanilloid (TRPV2), 69 Transient receptor potential vanilloid (TRPV5), 64–68, 249–250 338 Transient receptor potential vanilloid (TRPV6), 64–66, 69–70 Tumor suppressor silencing, 201–202 TWEAK, 128 U Unilateral ureteral obstruction (UUO), 266 Uremia-induced senescence, 136 Uremic cardiomyopathy aggravates stress-induced cardiomyopathy, 321–322 clinical manifestations definition, 313 epidemiology, 313–314 mechanism CKD-specific risk factors, 314, 315f conventional risk factors, 314, 315f IS and p-CS, 317 LV pressure overload, 314 LV volume overload, 314 phosphate retention, 318–319 secondary hyperparathyroidism, 314–316 vitamin D deficiency, 316 pathological cardiac remodeling, 273–274 CV disease, cause of, 272 indoxyl sulfate-induced myocardial hypertrophy, 275–276 intermediate mediator, 272 risk factors, 272, 273f stress-induced cardiac hypertrophy, 274–275 transgenic klotho-expression, 322–323 TRPC6 Calcineurin-NFAT pathway, 323 Klotho downregulation, 324 NFAT-responsive elements, 323 soluble Klotho inhibition, 324–325 WT and kl/+ mice, 322 Uremic toxins, 135–141 Index V Vascular calcification (VC), 139–141 Vascular endothelial growth factor (VEGF), 68–69, 248–249 Vascular medial calcification calcium and phosphate, 276–277 endothelium cells, 277–279, 278f vascular smooth muscle, 278f, 279–281 Vascular smooth muscle cells (VSMCs), 139–140 aortic α Klotho mRNA expression, 280, 281t beneficial effect, 279–280 contractile phenotype, 279–280 exogenous α Klotho/modulators, 280, 281t FGF23 augmented phosphate-induced aortic calcification, 279–280 mechanisms, 279–280 Runx2 and myocardin-serum response factor-dependent pathway, 279–280 viable intermittent system, 281 Vitamin D receptor agonists, 280 Vesicle-associated membrane protein (VAMP2), 186–187 Vitamin D receptor (VDR), 156 VSMCs See Vascular smooth muscle cells (VSMCs) W White matter, 224–226 Wite adipose tissue (WAT), 184 Wnt signaling, 127 X X-linked hypophosphatemic rickets (XLH), 163–164, 166 ... (FGFRs), and the fibroblast growth factor ligands, placing each in the context of its own family members while emphasizing Vitamins and Hormones, Volume 101 ISSN 0083-6729 http://dx.doi.org/10 .1016 /bs.vh.2016.02.008... the GCase activity of KLrP Vitamins and Hormones, Volume 101 ISSN 0083-6729 http://dx.doi.org/10 .1016 /bs.vh.2016.02.011 # 2016 Elsevier Inc All rights reserved Y Hayashi and M Ito ABBREVIATIONS... barrel in which Glu165 and Glu373 at the carboxyl termini of β-strands and could function as an acid/base catalyst and a nucleophile, respectively Actually, the mutants E165Q and E373Q lost the neutral